"The clinically meaningful overall response rate (ORR) and duration of response (DOR) in patients with crizotinib-resistant disease and the sustained CNS response reported from this study, as well as the good tolerability profile, support the additional development of this promising new ALK inhibitor," Sai-Hong Ignatius Ou, MD, PhD, of the Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA, and colleagues reported online in the Journal of Clinical Oncology.

Shrinkage of CNS metastases was observed following administration of oral alectinib 600 mg twice daily with an objective response rate (ORR) of 57% in patients who had measurable CNS metastases and a CNS complete response (CR) rate of 27% among all patients who had CNS metastases, said the investigators. The sustained durable response (median, 10.3 months) was prospectively assessed by an independent review committee (IRC).

Although crizotinib confers improved progression-free survival compared with chemotherapy in ALK-rearranged NSCLC, including those with CNS metastases, progression invariably occurs, they noted.

"Importantly, the cumulative incidence rate of CNS progression was lower than the cumulative incidence rate of non-CNS progression for all patients in this trial, which seems to suggest that alectinib can prevent or delay the emergence of CNS metastases," said Ou and colleagues.

The study showed that of the 23 patients with baseline CNS metastases (measurable or nonmeasurable) and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate (24.8%) was lower than the cumulative non-CNS progression rate (33.2%) for all patients.

Overall, the efficacy and safety profile of alectinib compared favorably with available data from other ALK inhibitors, said the investigators. Common adverse events (AEs) included myalgia, fatigue, constipation and peripheral edema. Most AEs were of grade 1 or 2.

"This active, potent ALK inhibitor provides another option for patients with ALK+ non-small cell lung cancer, in particular those with CNS metastases," Ranee Mehra, MD, of Fox Chase Cancer Centre in Philadelphia, PA, said in an interview. Mehra, who was not affiliated with the study, is in charge of ALK trials at Fox Chase. "Enrollment to clinical trials, including the future NCI ALK master protocol, continues to be important in this population to assess the impact of resistance mutations and the best sequencing of active agents," she told MedPage Today.

While Mehra acknowledged that tumor assessments outside the CNS were consistent among all patients, she also noted, as did the study authors, that only those patients who had baseline CNS metastases underwent protocol mandated brain imaging at regular intervals. "There may have been under-reporting of new asymptomatic CNS metastases," agreed Mehra.

In the study, 138 patients treated from June 2013 to April 2014 at 56 centers in 16 countries were evaluable for safety, progression free survival (PFS), and overall survival.

Patients were eligible for inclusion if they had locally advanced or metastatic NSCLC harboring an ALK rearrangement and had experienced progression while receiving crizotinib (Xalkori), as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients could be chemotherapy naive or could have received prior platinum-based chemotherapy. Most had received at least one prior line of platinum-based chemotherapy, pointed out the investigators.

Sixteen patients did not have RECIST-measurable target lesions so 122 patients were considered response evaluable (RE). The majority of patients (61%) had CNS metastasis at study entry, of whom 42% (35 of 84) had measurable CNS metastases and 73% (61 of 84) had received prior brain radiation, said the investigators.

ORR by IRC was 50% (95% CI, 41% to 59%), and the median duration of response (DOR) was 11.2 months (95% CI, 9.6 months to not reached), reported the investigators.

AEs included constipation (33%), fatigue (26%) and peripheral edema (25%). Myalgia was also observed but this usually had an early onset and generally resolved within 4 weeks of starting alectinib, the investigators said. Less than one quarter of patients required dose modification, and no grade 3 to 4 AE occurred in more than 5% of patients.

Alectinib is currently being investigated versus crizotinib in treatment-naive patients with advanced NSCLC and ALK rearrangement in a global randomized trial with PFS as the primary endpoint (NCT02075840), pointed out Ou and colleagues. "This trial will also prospectively examine performance of brain imaging on all enrolled patients at regular fixed-time intervals, regardless of the presence of brain metastases at baseline, and should provide additional evidence about whether alectinib, compared with crizotinib, will delay and/or prevent the emergence of CNS metastases," they said.

The observed CNS clinical activity of alectinib is consistent with the ob-served CNS ORR of 52% and the CNS CR rate of 29% in the dose-finding portion of the US phase I/II study (NP28761) of alectinib, said the investigators.

In addition, they noted that alectinib has been reported to be effective against leptomeningeal carcinomatosis in patients with ALK-positive NSCLC who experienced progression while receiving crizotinib alone or while receiving both crizotinib and ceritinib (Zykadia).

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